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PRODUCT MONOGRAPH
Pr
CLAFORAN®
Cefotaxime for injection, Mfr. Std.
1g and 2g cefotaxime (as cefotaxime sodium) per vial
β-lactam Antibiotic
sanofi-aventis Canada Inc.
2905 Place Louis-R-Renaud
Laval, Quebec H7V 0A3
Submission Control No.: 176886
Date of Revision:
November 12, 2014
s-a Version 6.0 dated November 12, 2014
PRODUCT MONOGRAPH
Pr
CLAFORAN®
Cefotaxime for injection, Mfr. Std.
1g and 2g cefotaxime (as cefotaxime sodium) per vial
β-lactam Antibiotic
ACTION AND CLINICAL PHARMACOLOGY
CLAFORAN (cefotaxime for injection) is a semi-synthetic, 2-aminothiazolyl cephalosporin
antibiotic for parenteral use. In vitro studies indicate that the antibacterial action of CLAFORAN
results from inhibition of cell wall synthesis. It is stable against the action of most β-lactamases.
INDICATIONS AND CLINICAL USE
Treatment
CLAFORAN (cefotaxime for injection) may be indicated for the treatment of infections caused
by susceptible strains of the designated micro-organisms in the diseases listed below.
Lower Respiratory Tract Infections:
Pneumonia and lung abscess caused by Streptococcus pneumoniae (formerly Diplococcus
pneumoniae), other streptococci (excluding enterococci, e.g. S. faecalis), Staphylococcus aureus
(penicillinase and non-penicillinase producing), Escherichia coli, Hemophilus influenzae,
(including ampicillin resistant strains) and unspecified Klebsiella species.
Urinary Tract Infections:
Caused by Escherichia coli, unspecified Klebsiella species (including K. pneumoniae), Proteus
mirabilis, indole positive Proteus, Serratia marcescens and Staphylococcus epidermidis. Also,
uncomplicated gonorrhea caused by N. gonorrhoeae including penicillin resistant strains.
Bacteremia/Septicemia:
Caused by Escherichia coli, unspecified Klebsiella strains and Serratia marcescens.
Skin Infections:
Caused by Staphylococcus aureus (penicillinase and non-penicillinase producing),
S. epidermidis, group A streptococci, Escherichia coli, Proteus mirabilis and indole positive
Proteus.
2
Intra-abdominal Infections:
Caused by Escherichia coli, and unspecified Klebsiella species.
Gynecological Infections:
Including pelvic inflammatory disease, endometritis and pelvic cellulitis caused by E. coli,
group A streptococci and Staphylococcus epidermidis; anaerobic bacteria including unspecified
Peptococcus and Peptostreptococcus strains and some strains of Bacteroides fragilis. In several
cases, although clinical cures were achieved, bacteriological follow-up was not available.
CLAFORAN, like other cephalosporins, has no activity against Chlamydia trachomatis.
Therefore, when cephalosporins are used in the treatment of patients with pelvic inflammatory
disease and C. trachomatis is one of the suspected pathogens, appropriate anti-chlamydial
coverage should be added.
Central Nervous System Infections:
Meningitis and ventriculitis caused by Haemophilus influenzae, Neisseria meningitidis,
Streptococcus pneumoniae, Klebsiella pneumoniae and Escherichia coli. CLAFORAN is not
active against Listeria monocytogenes.
Clinical experience with CLAFORAN in anaerobic infections is limited. CLAFORAN has been
used with some success in wound and intra-abdominal infections against some strains of
unidentified Bacteroides and anaerobic cocci.
CLAFORAN has been shown to be active against some strains of Pseudomonas.
In the treatment of infections encountered in immunosuppressed and granulocytopenic patients,
results of therapy with CLAFORAN have not been impressive.
CLAFORAN should not be considered in the treatment of enterococcal infections, i.e.
Streptococcus faecalis.
Specimens for bacteriologic culture should be obtained prior to therapy in order to isolate and
identify the causative organisms and to determine their susceptibilities to CLAFORAN. Therapy
may be instituted before results of susceptibility studies are known; antibiotic treatment should
be re-evaluated once these results become available.
3
Prophylactic use
The administration of CLAFORAN perioperatively (preoperatively, intra-operatively and
postoperatively) may reduce the incidence of certain infections in patients undergoing elective
surgical procedures (e.g. abdominal or vaginal hysterectomy, gastrointestinal and genitourinary
tract surgery) that may be classified as contaminated or potentially contaminated.
In patients undergoing caesarian section who are considered to be at increased risk of infection,
intraoperative (after clamping the umbilical cord) and postoperative use of CLAFORAN may
also reduce the incidence of certain postoperative infections.
Effective use for elective surgery depends on the time of administration (see DOSAGE AND
ADMINISTRATION section).
For patients undergoing gastrointestinal surgery, preoperative bowel preparation by mechanical
cleansing as well as with a non-absorbable antibiotic (e.g. neomycin) is recommended.
If there are signs of infection, specimens for culture should be obtained for identification of the
causative organism so that appropriate therapy may be instituted.
CONTRAINDICATIONS
CLAFORAN (cefotaxime for injection) is contraindicated in patients who have shown
hypersensitivity to cefotaxime sodium, the cephalosporin or the penicillin groups of antibiotics.
WARNINGS
Anaphylactic reactions
BEFORE THERAPY WITH CLAFORAN IS INSTITUTED, IT MUST BE CAREFULLY
DETERMINED WHETHER THE PATIENT HAS HAD PREVIOUS HYPERSENSITIVITY
REACTIONS TO CEFOTAXIME, CEPHALOSPORINS, PENICILLINS OR OTHER DRUGS.
SINCE CROSS ALLERGY EXISTS BETWEEN PENICILLINS AND CEPHALOSPORINS IN
5 TO 10 % OF CASES, CLAFORAN SHOULD BE GIVEN WITH EXTREME CAUTION TO
PATIENTS WITH TYPE 1 HYPERSENSITIVITY REACTIONS TO PENICILLIN.
ANTIBIOTICS, INCLUDING CLAFORAN SHOULD BE ADMINISTERED WITH
CAUTION TO ANY PATIENT WHO HAS DEMONSTRATED SOME FORM OF
ALLERGY, PARTICULARLY TO DRUGS. IF AN ALLERGIC REACTION TO CLAFORAN
OCCURS, THE DRUG SHOULD BE DISCONTINUED AND THE PATIENT TREATED
WITH THE USUAL AGENTS (E.G. EPINEPHRINE, ANTIHISTAMINES, PRESSOR
AMINES OR CORTICOSTEROIDS).
4
Speed of i.v. injection
During post-marketing surveillance, a potentially life-threatening arrhythmia was reported in
very few patients who received a rapid bolus injection of cefotaxime through a central venous
catheter. Therefore, cefotaxime should only be administered as instructed in the DOSAGE AND
ADMINISTRATION section.
Gastrointestinal
Clostridium difficile -associated disease
Clostridium difficile-associated disease (CDAD) has been reported with use of many
antibacterial agents, including CLAFORAN. CDAD may range in severity from mild diarrhea to
fatal colitis. It is important to consider this diagnosis in patients who present with diarrhea, or
symptoms of colitis, pseudomembranous colitis, toxic megacolon, or perforation of colon
subsequent to the administration of any antibacterial agent. CDAD has been reported to occur
over 2 months after the administration of antibacterial agents.
Treatment with antibacterial agents may alter the normal flora of the colon and may permit
overgrowth of Clostridium difficile. Clostridium difficile produces toxins A and B, which
contribute to the development of CDAD. CDAD may cause significant morbidity and mortality.
CDAD can be refractory to antimicrobial therapy.
If the diagnosis of CDAD is suspected or confirmed, appropriate therapeutic measures should be
initiated. Mild cases of CDAD usually respond to discontinuation of antibacterial agents not
directed against Clostridium difficile. In moderate to severe cases, consideration should be given
to management with fluids and electrolytes, protein supplementation, and treatment with an
antibacterial agent clinically effective against Clostridium difficile. Surgical evaluation should be
instituted as clinically indicated, as surgical intervention may be required in certain severe cases
(see ADVERSE REACTIONS section).
Hemolytic anemia
CLAFORAN SHOULD NOT BE USED IN PATIENTS WITH A HISTORY OF
CEPHALOSPORIN-ASSOCIATED
HEMOLYTIC
ANEMIA
SINCE
THE
RECURRENCE OF HEMOLYSIS IS MUCH MORE SEVERE.
An immune mediated hemolytic anemia has been observed in patients receiving cephalosporin
class antibacterials, including CLAFORAN. Severe cases of hemolytic anemia, including
fatalities, have been reported in both adults and children. If a patient develops anemia anytime
during, or within 2-3 weeks subsequent to the administration of CLAFORAN, the diagnosis of a
cephalosporin-associated anemia should be considered and the drug discontinued until the
etiology is determined.
5
Patients may benefit from periodic monitoring for signs and symptoms of hemolytic anemia,
including measurement of hematological parameters or drug-induced antibody testing, where
appropriate (see ADVERSE REACTIONS section).
PRECAUTIONS
CLAFORAN should be prescribed with caution in individuals with a history of lower
gastrointestinal disease, particularly colitis.
General
Prolonged use of CLAFORAN may result in the overgrowth of nonsusceptible organisms.
Constant evaluation of the patient's condition is essential. If superinfection occurs, therapy
should be discontinued and appropriate measures taken.
CLAFORAN, like other parenteral anti-infective drugs, may be locally irritating to tissues. In
most cases, perivascular extravasation of CLAFORAN responds to changing of the infusion site.
In rare instances, extensive perivascular extravasation of CLAFORAN may result in tissue
damage and require surgical treatment. To minimize the potential for tissue inflammation,
infusion sites should be monitored regularly and changed when appropriate.
Driving a vehicle or performing other hazardous tasks
In the case of side effects such as dizziness the patient's ability to concentrate and to react
properly may be impaired. In such cases patients should refrain from driving cars and using
machines.
Blood disorders
As with other β-lactam antibiotics, granulocytopenia, leukopenia, neutropenia and, more rarely,
bone marrow failure, pancytopenia, or agranulocytosis may develop during treatment with
CLAFORAN. For courses of treatment lasting longer than 10 days, blood counts should
therefore be monitored and treatment discontinuation should be considered in case of abnormal
results.
Use In Obstetrics
Cefotaxime crosses the placental barrier. However, the safety of CLAFORAN in pregnancy has
not been established and it should not be used during pregnancy.
Use of CLAFORAN in women of child-bearing potential requires that the anticipated benefits be
weighed against the possible risks.
6
Nursing Mothers
Since cefotaxime is excreted in human milk in low concentrations, either breast feeding or
treatment of the mother should be discontinued as necessary.
Patients with Special Diseases and Conditions
Although CLAFORAN rarely produces alterations in kidney function, evaluation of renal status
is recommended, especially in severely ill patients receiving high doses.
Patients with markedly impaired renal function should be placed on the special dosage schedule
recommended under DOSAGE AND ADMINISTRATION section, because normal dosage in
these individuals is likely to produce excessive and prolonged serum antibiotic concentrations. If
CLAFORAN and aminoglycosides are to be administered to the same patient, these antibiotics
should be administered separately and not as a mixed injection (see DOSAGE AND
ADMINISTRATION, Reconstitution, Incompatibilities section). Renal function must be
monitored in all such cases.
The sodium content of cefotaxime sodium (48.2 mg/g) should be taken into account in patients
necessitating sodium restriction.
Drug Interactions
Probenecid interferes with the renal tubular transfer of cephalosporins, thereby delaying their
excretion and increasing their plasma concentrations.
As with other cephalosporins, cefotaxime may potentiate the nephrotoxic effects of nephrotoxic
drugs (such as furosemide, aminoglycosides).
Drug - Laboratory Tests Interactions
Positive direct Coombs' test is known to develop in individuals during treatment with the
cephalosporin group of antibiotics, including cefotaxime sodium.
In laboratory tests a false positive reaction to glucose may occur with reducing substances but
not with the use of specific glucose oxidase methods.
7
ADVERSE REACTIONS
Clinical Trials Adverse Drug Reactions
The most frequent adverse reactions with their frequency of occurrence are:
Central Nervous System (0.2%):
Headache
Gastrointestinal (1.7%):
Colitis, diarrhea, nausea and vomiting. Symptoms of pseudomembranous colitis can appear
during or after CLAFORAN treatment.
Genitourinary System ( <1%):
Moniliasis, vaginitis.
Hematologic System (<1%):
As with other β-lactam antibiotics, neutropenia and, more rarely, agranulocytosis may develop
during treatment with CLAFORAN, particularly if given over long periods. Furthermore,
transient leukopenia, eosinophilia and thrombocytopenia have also been reported.
Some individuals have developed positive direct Coombs' test during treatment with
CLAFORAN and other cephalosporin antibiotics (see PRECAUTIONS, Laboratory tests
section). Rare cases of hemolytic anemia have been reported.
Hypersensitivity (1.8%):
Rash, pruritus, fever.
Kidney (<1%):
Increased BUN has occasionally been observed.
Liver (<1%):
Transient elevations in SGOT, SGPT, serum LDH, and serum alkaline phosphatase levels have
been reported.
Local (5%):
Injection site inflammation with intravenous administration. Pain, induration and tenderness after
intramuscular injection.
Other Adverse Events including Post-Marketing Surveillance Data
Anaphylactic reactions:
Angioedema, bronchospasm, malaise possibly culminating in shock, may rarely occur (see
WARNINGS, Anaphylactic reactions section).
8
Cardiovascular:
Potentially life-threatening arrhythmia following rapid bolus infusion has been reported in very
few patients who received rapid intravenous administration of CLAFORAN through a central
venous catheter (see WARNINGS, Speed of i.v. injection section).
Central Nervous System:
Administration of high doses of β-lactam antibiotics, including CLAFORAN, particularly in
patients with renal insufficiency may result in encephalopathy (e.g. impairment of consciousness,
abnormal movements and convulsions). Headache and dizziness have been reported.
Cutaneous:
Rash, pruritus and less frequently urticaria. As with other cephalosporins, isolated cases of
bullous eruptions (erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis)
have been reported.
Cases of acute generalized exanthematous pustulosis (AGEP) have been reported.
Gastrointestinal:
During treatment with CLAFORAN, abdominal pain may occur. As with all other broad
spectrum antibiotics diarrhea may sometimes be a symptom of enterocolitis, which may, in some
cases, be accompanied by blood in stools. A particular form of enterocolitis that can occur with
antibiotics, including CLAFORAN, is Clostridium difficile-associated disease (see
WARNINGS, Gastrointestinal, Clostridium difficile associated disease section).
General disorders and administration site conditions:
Cases of pain at the injection site (for IM formulation); inflammatory reactions at the injection
site (including phlebitis/thrombophlebitis) have been reported.
Hematologic System:
Cases of immune hemolytic anemia have been observed (see WARNINGS, Hemolytic Anemia
section). Cases of bone marrow failure, pancytopenia, neutropenia and agranulocytosis have
been reported (see PRECAUTIONS, Blood disorders).
Renal:
Decreases in renal function (increase of creatinine) have been observed with cephalosporins
including CLAFORAN, particularly when co-prescribed with aminoglycosides.
As with some other cephalosporins, rare cases of interstitial nephritis have been reported in
patients treated with CLAFORAN.
Cases of acute renal failure have been reported.
9
Liver:
Increase in liver enzymes (ALT, AST, LDH, gamma-GT and/or alkaline phosphatase) and/or
bilirubin have been reported. These laboratory abnormalities, which may also be explained by
the infection, may rarely exceed twice the upper limit of the normal range and elicit a pattern of
liver injury, usually cholestatic and most often asymptomatic. Hepatitis (sometimes with
jaundice) has been reported.
Other:
Superinfection: as with other antibiotics, the use of CLAFORAN, especially if prolonged, may
result in overgrowth of non-susceptible organisms. Repeated evaluation of the patient’s
condition is essential. If superinfection occurs during therapy, appropriate measures should be
taken.
As reported with other antibiotics for the treatment of borreliosis a Jarisch-Herxheimer reaction
may develop during the first days of treatment.
The occurrence of one or more of the following symptoms has been reported after several weeks
of treatment of borreliosis: skin rash, itching, fever, leucopenia, increase in liver enzymes,
difficulty of breathing, joint discomfort. To some extent, these manifestations are consistent with
the symptoms of the underlying disease for which the patient is being treated.
SYMPTOMS AND TREATMENT OF OVERDOSAGE
For management of a suspected drug overdose, contact your regional Poison Control Centre.
There is a risk of reversible encephalopathy in cases of administration of high doses of β-lactam
antibiotics including CLAFORAN.
10
DOSAGE AND ADMINISTRATION
CLAFORAN (cefotaxime for injection) may be administered intramuscularly or intravenously
after reconstitution (see Tables 3 and 4 with recommended mode of reconstitution according to
route of administration).
Dosage
Treatment for adults and children with body weight of 50 kg or more:
The dosage of CLAFORAN should be determined by susceptibility of the causative organisms,
severity of the infection and condition of the patient.
Table 1 ­ Guidelines for dosage of CLAFORAN for adults and children with body weight of 50 kg or more.
Type of Infection
Daily Dose (g)
Frequency and Route
Uncomplicated gonorrhea
1
1 g i.m. single dose
Uncomplicated infections
2
1 g every 12 hours
i.m. or i.v.
Moderately severe to severe infections
3-6
1-2 g every 8 hours
i.m. or i.v.
Very severe infections (e.g. septicemia,
CNS)
6-8
2 g every 6-8 hours i.v.
up to 12
2 g every 4 hours i.v.
Life-threatening infections
THE MAXIMUM DAILY DOSAGE SHOULD NOT EXCEED 12 GRAMS.
Treatment for Neonates, Infants, and Children:
The following dosage schedule is recommended:
Neonates (birth to 1 month)
0-1 week of age:
1-4 weeks of age:
50 mg/kg per dose i.v. every 12 hours
50 mg/kg per dose i.v. every 8 hours
Infants and children (1 month to 12 years)
For body weights less than 50 kg, the recommended daily dose is 50 to 100 mg/kg i.m. or i.v.
divided into 4 to 6 equal doses, or up to 180 mg/kg/day for severe infections (including central
nervous system infections).
For body weights of 50 kg or more, the usual adult dosage should be used; THE MAXIMUM
DAILY DOSAGE SHOULD NOT EXCEED 12 GRAMS.
11
Table 2 ­ Guidelines for dosage of CLAFORAN for neonates, infants and children.
Patients
Age or weight
Dose
Route
Dose interval
Neonates
0 to 1 week
50 mg/kg/dose
IV
Every 12 hours
Neonates
1 to 4 weeks
50 mg/kg/dose
IV
Every 8 hours
Infants and
Children
< 50 kg
50 to 100 mg/kg/day
(up to 180 mg/kg/day for severe
infections, including meningitis)
IV or
IM
Divided into 4
to 6 equal
doses
Children
≥ 50 kg
adult dosage
Duration of Treatment:
Administration of CLAFORAN should be continued for a minimum of 48 to 72 hours after the
patient defervesces or after evidence of bacterial eradication has been obtained; a minimum of 10
days of treatment is recommended for infections caused by Group A beta-hemolytic streptococci
in order to guard against the risk of rheumatic fever or glomerulonephritis; frequent bacteriologic
and clinical appraisal is necessary during therapy of chronic urinary tract infections and may be
required for several months after therapy has been completed; persistent infections may require
prolonged treatment. Doses less than those recommended should not be employed.
Prophylactic use:
Surgery patients
To prevent postoperative infection in contaminated or potentially contaminated surgery,
recommended doses are as follows:
•
1 g i.m. or i.v. administered 1/2 to 1 1/2 hours prior to the initial surgical incision to ensure
that adequate antibiotic levels are present in the serum and tissues at the start of surgery
•
1 g i.m. or i.v. administered 1 1/2 to 2 hours following the first dose; for lengthy operative
procedures, additional intraoperative doses may be administered, if necessary, at appropriate
intervals (1 1/2 to 2 hours) during surgery
•
1 g i.m. or i.v. administered within 2 hours following completion of surgery
The total cumulative prophylactic dose should not exceed 6 g in a 12-hour period.
Caesarian Section Patients
The first dose of 1 g is administered i.v. as soon as the umbilical cord is clamped. The second
and third doses should be given as 1 g i.m. or i.v. at 6 and 12 hours after the first dose.
12
Dosage for Patients with Impaired Renal Function:
In patients with estimated creatinine clearance of less than 20 mL/min/1.73m2 the dose of
CLAFORAN should be halved (see PRECAUTIONS, Patients with Special Disease and
Conditions section).
If serum creatinine values alone are available, the following formula (based on sex, weight, and
age of the patient) may be used to convert these values into creatinine clearance.
Weight (kg) x (140 - age in years)
72 x serum creatinine (mg/dl)
Males:
ClCr (ml/min) =
Females:
ClCr (ml/min) = 0.85 x above value
In hemodialysed patients
1 to 2 g daily, depending on the severity of the infection; on the day of haemodialysis,
CLAFORAN must be administered after the dialysis session.
Administration
Intramuscular:
CLAFORAN should be injected well within the body of a relatively large muscle such as the
upper outer quadrant of the buttock (i.e. gluteus maximus); aspiration is necessary to avoid
inadvertent injection into a blood vessel.
Intravenous:
The intravenous route is preferable for patients with bacteremia, bacterial septicemia, or other
severe or life-threatening infections, or for patients who may be poor risks because of lowered
resistance resulting from such debilitating conditions as malnutrition, trauma, surgery, diabetes,
heart failure, or malignancy, particularly if shock is present or impending.
For bolus administration, the solution containing CLAFORAN must be injected over a period of
3 to 5 minutes (see WARNINGS, Speed of i.v. injection section).
Using an infusion system, it may also be given over a longer period of time through the tubing
system by which the patient may be receiving other intravenous solutions. Butterfly 1* or scalp
vein type needles are preferred for this type of infusion. However, during infusion of the solution
containing CLAFORAN, it is advisable to discontinue temporarily the administration of other
solutions at the same site (see DOSAGE AND ADMINISTRATION, Reconstitution,
Incompatibilities section).
1
*Reg’d TM of Abbott Laboratories
13
Reconstitution
For Intramuscular Use:
CLAFORAN should be reconstituted with Sterile Water for injection or Bacteriostatic Water for
injection in accordance with the volumes recommended in the following table.
Table 3 ­ Reconstitution table for intramuscular use
Volume to be Added
to Vial (mL)*
Approximate
Available vol. (mL)
Approx. Average
Concentration
(mg/mL)
1 g vial
3
3.4
300
2 g vial
5
6.0
330
* shake to dissolve
For Intravenous Use:
For intravenous bolus use
1 g and 2 g vials should be reconstituted with at least 10 mL of Sterile Water for injection.
For intravenous infusion use
Reconstituted solution may be further diluted with 50 to 1000 mL of the fluids recommended for
i.v. infusion.
Table 4 ­ Reconstitution table for intravenous use
Volume to be Added
to Vial (mL)*
Approximate
Available vol. (mL)
Approx. Average
Concentration
(mg/mL)
1 g vial
10
10.4
95
2 g vial
10
11.0
180
* shake to dissolve
A solution of 1 g of CLAFORAN in 14 mL of Sterile Water for Injection is isotonic.
14
Solutions For i.v. Infusion:
Claforan is compatible with the following infusion fluids:
- 0.9% NaCl injection
- 5% Dextrose injection
- 0.9% NaCl and 5% Dextrose injection
- 0.45% NaCl and 5% Dextrose injection
- 0.2% NaCl and 5% Dextrose injection
- Sodium Lactate injection
- 5% Dextrose and 0.15% KCl injection
- Plasma-Lyte 56 Electrolyte Solution in 5% Dextrose injection
- Ringer's injection
- Lactated Ringer's solution
- Lactated Ringer's with 5% Dextrose injection
Incompatibilities:
Solutions of CLAFORAN must not be admixed aminoglycoside solutions. If CLAFORAN and
aminoglycosides are to be administered to the same patient, they must be administered separately
and not as a mixed injection.
Solutions of CLAFORAN should not be prepared with diluents having a pH above 7.5 such as
Sodium Bicarbonate Injection.
STABILITY AND STORAGE RECOMMENDATIONS
CLAFORAN in the dry state should be stored at room temperature (15-25oC), protected from
light and heat.
CLAFORAN reconstituted in the original vial as described under Reconstitution is chemically
stable for 12 hours at room temperature (15-25oC) and for 24 hours under refrigeration (2-8 oC).
Only freshly prepared reconstituted solutions may be further diluted with 50 to 1000 mL of the
recommended infusion fluids in VIAFLEX**2 intravenous bags. Such solutions are chemically
stable for 12 hours at room temperature (15-25oC) and for 24 hours under refrigeration (2-8 oC).
Any unused solutions should be discarded.
From a microbiological point of view, this infusion preparation should be used immediately. If
not used immediately, in-use storage times and conditions prior to use are the responsibility of
the user and cannot be longer than 24 hours at 2°C to 8°C or 12 hours at room temperature (1525°C) when dilution has taken place in controlled and validated aseptic conditions.
2
* Reg’d TM of Baxter-Travenol Laboratories
15
Solutions of CLAFORAN range from light yellow to amber, depending on concentration and the
diluent used. The solutions tend to darken depending on storage conditions and should be
protected from elevated temperatures and excessive light.
CLAFORAN solutions exhibit maximum stability in the pH 5-7 range.
Special Instructions
Parenteral drug products should be inspected visually for particulate matter and discoloration
prior to administration. Solutions of CLAFORAN range from light yellow to amber, depending
on concentration and diluent used. The dry powder as well as solutions tend to darken,
depending on storage conditions.
AVAILABILITY OF DOSAGE FORMS
CLAFORAN (cefotaxime for injection) is supplied as a sterile, creamy white powder, in vials
containing 1.0 and 2.0 g of cefotaxime (as cefotaxime sodium).
Composition
CLAFORAN (cefotaxime for injection) does not contain any additives or other inactive
ingredients.
16
PHARMACEUTICAL INFORMATION
Drug substance
Common Name:
cefotaxime sodium
Chemical Name:
5-Thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid,
3- (acetyloxy)methyl -7-[[(2-amino-4-thiazolyl)
(methoxyimino) acetyl]amino]-8-oxo-, monosodium salt,
[6R [6α, 7β(Z)]]
Structural Formula:
Molecular Formula:
C16H16N5NaO7S2
Molecular Weight:
477.5
Description:
Creamy white crystalline powder.
It is soluble in water at about 20%, but poorly soluble in
common organic solvents including ethanol.
17
MICROBIOLOGY
Cefotaxime has in vitro activity against a wide range of Gram-positive and Gram-negative
organisms as observed in the following table.
Table 5 ­ Summary for sensitivity of aerobic and anaerobic bacteria to cefotaxime
MICROORGANISMS
No. of
CUMULATIVE PERCENTAGE OF STRAINS INHIBITED AT
strains
INDICATED CONCENTRATIONSa (μg/mL)
0.5
1.0
2.0
4.0
8.0
16
32
64
≤0.1
AEROBES
GRAM-NEGATIVE
Acinetobacter spp.
39
5
10
18
28
38
62
72
87
90
Acinetobacter anitratum
154
6
13
43
71
83
87
Acinetobacter Iwoffii
15
50
90
100
Citrobacter spp.
47
60
74
74
77
79
85
89
94
98
Citrobacter diversus
25
100
Citrobacter freundii
28
79
93
96
100
Enterobacteriacae spp.
6083
91
95
99
100
Enterobacter spp.
61
79
90
95
98
100
Enterobacter aerogenes
57
88
89
91
95
98
100
Enterobacter cloacae
80
63
69
74
84
88
94
b
657
95
98
99
100
Escherichia coli
Haemophilus spp.b
b
Haemophilus influenzae
Klebsiella spp.
Klebsiella oxytoca
b
Klebsiella pneumoniae
Neisseria spp.
Neisseria gonorrhoeaeb
Neisseria meningitidis
Proteus indole (+)
Proteus indole (-)
Proteus mirabilis (-)
Providencia spp.
Pseudomonas spp.
Pseudomonas aeruginosa
Pseudomonas maltophilia
Pseudomonas putida
Salmonella spp.
Salmonella typhi
Serratia spp.
Serratia marcescensb
Shigella spp.
AEROBES
GRAM-POSITIVE
Staphylococcus aureus
Staphylococcus epidermidis
Streptococcus group A
Streptococcus group B
Streptococcus enterococcus
294
97
99
100
113
96
98
99
101
10
226
91
97
98
50
100
60
88
100
20
99
12
472
75
100
100
64
90
98
35
75
85
50
94
90
96
95
99
54
1
78
≥128
100
100
100
100
100
150
102
20
186
37
136
1412
12
10
33
30
93
86
79
100
29
35
97
43
41
47
44
52
50
19
74
84
95
100
1686
175
12
20
146
20
100
90
5
45
16
57
100
1
5
100
86
3
1
95
9
6
70
80
90
97
28
30
100
57
69
100
100
100
72
85
50
85
97
90
90
100
100
100
100
78
100
95
100
50
100
18
54
65
58
81
89
73
95
89
100
99
10
14
17
63
97
100
20
21
25
100
Table 5 ­ Summary for sensitivity of aerobic and anaerobic bacteria to cefotaxime
MICROORGANISMS
No. of
CUMULATIVE PERCENTAGE OF STRAINS INHIBITED AT
strains
INDICATED CONCENTRATIONSa (μg/mL)
0.5
1.0
2.0
4.0
8.0
16
32
64
≤0.1
Streptococcus group D
23
70
87
98
100
non-enterococcus
Streptococcus pneumoniae
67
91
ANAEROBES
GRAM-NEGATIVE
Bacteroides spp
51
4
20
26
38
60
82
94
Bacteroides fragilis
28
50
90
Bacteroides thetaiotaomicron
13
50
90
ANAEROBES
GRAM-POSITIVE
Clostridum spp.
13
15
61
84
100
(Other than C. difficile)
Clostridium perfringens
19
50
90
Cocci
11
50
90
Propionibacterium
11
90
a
Serial dilutions (broth and agar methods)
b
Includes producers and non-producers of β-lactamases.
≥128
100
The sensitivity to β-lactamases was determined by a cell-free in vitro test system using
characteristic β-lactamases of various Richmond classes. Evidence was found of the stability of
cefotaxime against the inactivating effect of cephalosporinases from Enterobacter cloacae P 99
(class Ia) and Pseudomonas HS 18 (Id), as well as against that of the β-lactamase from
Escherichia coli TEM (IIIa). The test compound was mildly sensitive to the effects of the
enzyme formed by Klebsiella aerogenes 1082 E (Ivc).
Table 6 ­ Effect of ß-lactamase on cefotaxime
E. cloacae P99
Cefotaxime
Relative ßlactamase
sensitivity
MIC
0%
125 µg
Ps. Aeruginosa
HS18
Relative ß- MIC
lactamase
sensitivity
0%
1.0 µg
K1. aerogenes
1082E
Relative ß- MIC
lactamase
sensitivity
2.5%
12.5 µg
E. coli TEM
Relative ßlactamase
sensitivity
0%
MIC
0.078 µg
Initial count for each organism about 5 x 10-4 CFU per mL in each tube. There is in vitro
evidence of synergy between cefotaxime and aminoglycoside antibiotics (gentamicin and
tobramycin) against some strains of Pseudomonas.
19
A broth dilution checkerboard synergy assay was used to assess the activity of cefoperazone,
cefotaxime, moxalactam, and carbenicillin, in combination with tobramycin, against 38 strains of
Pseudomonas aeruginosa. Synergy occurred significantly more often (p < 0.001) when
tobramycin was combined with cefotaxime (63%) than when it was combined with carbenicillin
(26%), cefoperazone (21%), or moxalactam (18%). Of the 25 synergistically inhibited strains,
the combination cefotaxime-tobramycin was synergistic against 24 and was the only synergistic
combination against 10. Of six strains initially resistant to cefotaxime, five were susceptible to
this agent (minimum inhibitory concentration, 32 µg /mL) when it was combined with
tobramycin.
Table 7 ­ Results of synergy testing against 38 strains of Pseudomonas aeruginosa
a
Antibiotic combination
T + CTb
T + CB
T + CP
T + ML
a
T
(tobramycin)
CT (cefotaxime)
CB (carbenicillin)
CP (cefoperazone)
ML (moxalactam)
b
No. (%) synergistic
24 (63.2)
10 (26.3)
8 (21.1)
7 (18.4)
p < 0.001 for T + CT vs each of the other combinations (McNemar test). Differences
among the other antibiotic combinations were not statistically significant.
In another study the combination cefotaxime/gentamicin was tested against 111 clinical isolates
of Pseudomonas aeruginosa and was found to have a synergistic effect against 73.9% of the
strains tested.
Susceptibility Tests
With the Bauer-Kirby-Sherris-Turck method of disc susceptibility testing, a disc containing
30 µg of cefotaxime should give a zone of at least 20 mm for microorganisms to be considered
susceptible to CLAFORAN, 15-19 mm for organisms of intermediate susceptibility and a zone
of 14 mm or less for cefotaxime resistant organisms.
Because certain strains of enterobacteriaceae have been shown to be resistant to the
cephalosporin class disc, only the cefotaxime discs must be used for testing the susceptibility of
CLAFORAN.
20
PHARMACOLOGY
Animal Pharmacology
Animal pharmacology studies demonstrate that cefotaxime has no significant effect on the
central nervous system, cardiovascular system, respiratory system, kidneys, blood clotting
mechanisms and blood glucose levels.
Human Pharmacology and Kinetics
Intramuscular administration:
Single dose
Following intramuscular administration of a single 500 mg or 1 g dose of CLAFORAN to
normal volunteers, mean peak serum concentrations of 11.7 and 20.5 μg/mL respectively, are
attained within 30 minutes and decline with an elimination half-life of approximately 1 hour.
Figure 1 ­ Mean serum concentrations and urinary excretion data of cefotaxime administered
intramuscularly as a single dose of 0.5 g and 1.0 g in 14 healthy male volunteers
21
Table 8 ­ Pharmacokinetic parameters of cefotaxime after single intramuscular administration in 14
healthy male volunteers (mean)
Cefotaxime
KINETIC PARAMETERS
Peak serum level (μg/mL)
Time to peak (h)
AUC (0- ∞) (μg /mL/h)
t1/2 ß (h)
Cl S (mL/min/1.73m2)
% unchanged drug in urine / 0-24 h
Cl r (mL/min/1.73m2)
500 mg
11.7
0.4
24.1
1.2
315.6
38.8
122.4
1000 mg
20.5
0.5
48.4
1.3
318.5
33.3
103.8
Multiple doses
Following multiple intramuscular injections, serum levels at 30 minutes after a dose of 500 mg
every 8 hours, ranged from 9.2 to 11.9 μg/mL. There was no difference between the half-life (h)
at Day 1 and Day 11, but differences were noted in the AUC 0-8 h, fractional serum clearance and
renal clearance; the latter probably being related to significantly lower recovery of the drug on
Day 11.
Drug administration time
Figure 2 ­ Mean serum levels ± SE of cefotaxime administered intramuscularly after multiple doses of 500 mg
every 8 hours in 30 healthy male volunteers.
22
Table 9 ­ Pharmacokinetic parameters of cefotaxime after multiple intramuscular injections of 500 mg (mean
± SE) in 30 healthy male volunteers.
Day 1
0.778 ± 0.04
0.93 ± 0.05
24.28 ± 1.18
304.8 ±13.49
23.96 ±1.07
194.4 ±18.35
62.6 ±5.09
-1
Elimination rate constant (ß) (h )
t1/2 (h)
AUC (0-8 h) (μg /mL/h)
Serum clearance (mL/min/1.73m2)
Volume of distribution (L/1.73m2)
Renal clearance (mL/min/1.73m2)
Drug excreted (0-6 h) (%)
Day 11
0.784± 0.04
0.92± 0.05
19.9 ±1.25
377.3 ± 23.61
29.68 ± 2.58
146.6 ±13.86
39.1± 3.77
Intravenous administration:
Single dose (bolus over 5 minutes)
Following intravenous administration (bolus) of a single 500 mg, 1 g and 2 g dose of
CLAFORAN to healthy adult male volunteers, the serum levels were 38.9, 101.7, and
214.4 μg/mL respectively, without alteration in the elimination half-life.
Figure 3 ­ Mean serum concentrations and urinary excretion data of cefotaxime administered intravenously
(over a 5 min. period) as a single dose of 0.5 g, 1 g and 2 g in 15 healthy male volunteers.
23
Table 10 ­ Pharmacokinetic parameters of cefotaxime after intravenous administration of a single dose of
0.5 g, 1 g and 2 g in 15 healthy male volunteers (mean).
KINETIC PARAMETERS
Peak serum level (μg/mL)
AUC (0-∞ ) (μg /mL/h)
t1/2 ß (h)
Cls (mL/min/1.73m2)
500 mg
38.9
30.6
1.04
245.3
% unchanged drug in urine/0-24 h
Clr (mL/min/1.73m2)
59.3
146.8
Cefotaxime
1000 mg
2000 mg
101.7
214.4
70.4
134.1
1.05
0.86
206.8
215.1
51.3
104.0
51.3
110.4
Single dose (infusion over 30 minutes)
Administration of 1 g of CLAFORAN infused intravenously over 30 minutes gave mean peak
serum concentrations at the end of the 30 minutes of 41.1 μg/mL with an elimination half-life of
1.13 h.
Figure 4 ­ Mean serum concentrations and urinary excretion data of cefotaxime infused intravenously over 30
min. as a single dose of 1.0 g in 10 healthy male volunteers.
24
Table 11 ­ Pharmacokinetic parameters after single intravenous infusion over 30 min. of 1 g cefotaxime in 10
healthy male volunteers (mean)
KINETIC PARAMETERS
Peak serum level at the end of 30 min. infusion (μg/mL)
AUC (0-∞) (μg/mL/h)
t1/2 ß (h)
Cls (mL/min/1.73m2)
% unchanged drug in urine/0-24 h
Clr (mL/min/1.73m2)
Cefotaxime
1000 mg
41.1
44.3
1.13
341.6
40.0
130.1
Multiple dose (repetitive i.v infusion over 30 minutes)
There was no evidence of drug accumulation following repetitive i.v. infusions over 30 minutes
of 1 g doses every 6 hours for 14 days.
The biological half-life was approximately 1.0 hour and the 24 hours urinary excretion of
unchanged drug amounted to 62.6% of the administered dose (almost all of it in the first
6 hours).
Figure 5 ­ Mean serum concentrations and urinary excretion data of cefotaxime infused intravenously over 30
min. as a single dose of 1.0 g, every 6 hours for 14 days in 16 healthy male volunteers.
25
Table 12 ­ Pharmacokinetic parameters of cefotaxime after repetitive intravenous infusion (over 30 min.) of
1.0 g doses every 6 hours, for 14 days in 16 healthy male volunteers (mean).
1000 mg Cefotaxime
Day 1
Day 15
57.4
68.9
1.2
1.0
259.3
219.5
58.9
61.1
154.5
132.9
KINETIC PARAMETERS
AUC (0- ∞ ) (μg /mL/h)
T1/2 ß (h)
Cls (mL/min/1.73m2)
% unchanged drug in urine/0-6 h
Clr (mL/min/1.73m2)
Cerebrospinal Fluid Penetration:
Children
In 13 children (9 days to 5 years) successfully treated for bacterial meningitis with a dose of
40 mg/kg, iv, every 6 hours for 14 days, cefotaxime diffused consistently and in therapeutic
levels into the cerebrospinal fluid. Cerebrospinal fluid levels of 6.0 μg/mL (after 36-48 h) and
1.2 μg/mL (after 14 days) in treatment were 17 to 275 - fold the MBCs for the infecting
organisms. After a single 40 mg/kg dose to each of 5 infants (1 to 19 months) with
ventriculostomies, mean cerebrospinal fluid levels of cefotaxime were 6.4, 5.7 and 4.5 μg/mL at
2, 4 and 6 hours, respectively. Cefotaxime mean half-life in 4 infants was 1.15 ± 0.58 h in
plasma and 4.3 ± 3.1 h in cerebrospinal fluid.
Table 13 ­ Cefotaxime and desacetyl cefotaxime plasma and CSF levels after i.v. injection in 13 children with
bacterial meningitis
Drug level (μg/mL)*
Early (36 to 48 h)
Drug
Cefotaxime
Desacetyl
cefotaxime
Plasma
5.1 – 55.7
(16.7 ± 14.7)
2.5 – 20.1
(8.1 ± 4.2)
CSF
0.74 – 38.8
(6.0 ± 10.2)
0.89 – 27.4
(4.6 ± 7.0)
Diffusion
ratio (%)
7.0 – 69.7
(27.7 ± 16.2)
12.2 – 219
(51.9 ± 54.5)
Plasma
1.7 – 13.6
(6.6 ± 4.3)
1.5 – 9.5
(5.4 ± 1.9)
Late (14 days)
Diffusion ratio
CSF
(%)
0.6 – 3.1
4.5 – 64.7
(1.2 ± 0.9)
(25.7 ± 21)
0.5 – 2.1
8.9 – 40.0
(1.1 ± 0.8)
(20.8 ± 9.3)
*Values in parenthesis represent the mean ± standard deviation
Adult
Thirty-two (32) cases of adult meningitis received cefotaxime, 2 g every 8 hours by bolus
injection (3-5 minutes). Mean concentration of cefotaxime in cerebrospinal fluid ranged from
0.8 μg/mL (aseptic meningitis), to 6.4 μg/mL (Gram-negative and Listeria monocytogenes), and
from 0.5 to 5.4 μg/mL for the metabolite.
Paediatric Pharmacokinetics:
A single 50 mg/kg dose of cefotaxime was administered as an intravenous infusion over a 10 to
15 minute period to 29 newborn infants grouped according to birth weight and age. The mean
26
half-life of cefotaxime in infants with lower birth weight (less than or equal to 1500 g),
regardless of age, was longer (4.6 hours) than the mean half-life (3.4 hours) in infants whose
birth weight was greater than 1500 g. Mean serum clearance was also smaller in the lower birth
weight infants. Although the differences in mean half-life values are statistically significant for
weight, they are not clinically important. Therefore, dosage should be based solely on age (see
DOSAGE AND ADMINISTRATION, Treatment for Neonates, Infants and Children:
section).
Table 14 ­ Pharmacokinetic parameters in 29 newborns receiving single intravenous dose of 50 mg/kg
cefotaxime (mean)
(≤ 1500 g at
birth and
< 5 days old)
Group I
Group II
Group III
(> 1500 g at
birth and
< 5 days old)
(varying birth
weight and
≥ 5 days old)
(≤ 1500 g)
(> 1500 g)
116
127
122
133
117
394
418
375
400
392
683
620
551
675
561
Peak serum
concentration
(μg/ml)
AUC 0-6 h
(μg/ml/h)
AUC 0- ∞
(μg/ml/h)
Group A
Group B
(1)
Half-life (h)
4.9
3.7
3.5
4.6
(1)
3.4
(2)
(2)
Vd (L/kg)
0.53
0.44
0.45
0.51
0.44
(2)
(2)
(1)
Cls
(mL/min/1.73m2)
22.5
38.8
39.1
(1)
23.0
43.9
(3)
(1)
(1) p ≤ 0.05; (2) p ≤ 0.01; (3) p ≤ 0.001
Renal insufficiency:
1g of cefotaxime was injected intravenously b.i.d. for 4 to 7 days in 9 patients with renal
insufficiency whose creatinine clearances ranged from 5.0 to 25.5 mL/min/1.73m2.
27
Table 15 ­ Pharmacokinetic parameters of cefotaxime and its metabolites in 9 patients with renal
insufficiency after repeated intravenous administration (mean)
CEFOTAXIME
Peak plasma level (μg/mL)
First
dose
C max lastdose
C max firstdose
Time-to-peak (h)
Distribution half-life (h)
Biological half-life (h)
AUC 0- ∞ ( μg /mL/h)
First
dose
19.3
1.2
0.5
2.9
280
AUC (0 − 12h)lastdose
AUC (0 − 12h) firstdose
Renal clearance (mL/min)
Cumulative urinary excretion
(mg)
last
dose
DACM
First
dose
5.0
2.0
0.7
3.1
351
last
dose
17.2
First
dose
4.5
4.2
last
dose
14.7
3.9
3.7
6.5
6.0
6.2
6.0
10.4
331
11.5
722
6.2
106
16.6
605
8.1
115
21.1
538
1.7
14.8
127.8
137.7
UP2
5.1
1.3
13.0
171.4
last
dose
37.3
UP1
3.1
154.4
30.2
84.5
3.0
142.0
30.9
75.3
The half-lives of cefotaxime, desacetyl (DACM), and UP1 and UP2 were longer and renal
clearances were decreased in these patients. The biological half-life of cefotaxime was 2.9 hours
after the first dose and 3.1 hours after the 5th dose. Neither the drug nor its metabolites
accumulated even when clearances were as low as 20 mL/min/1.73m2.
However, in patients with creatinine clearances approaching 5 mL/min/1.73m2, accumulation of
the metabolites becomes apparent.
Consequently, until further clinical experience is obtained in such patients, it is recommended
that the dose of cefotaxime be halved when creatinine clearance is lower than 20 mL/min/1.73m2
(see DOSAGE AND ADMINISTRATION, Dosage for Patients with Impaired Renal
Function: section).
Metabolism and Excretion:
Cefotaxime is partially metabolized in humans by non-specific esterases which desacetylate the
acetoxymethyl side chain to form desacetyl cefotaxime (DACM). Desacetylation is followed by
formation of the lactone and subsequent conversion to open β-lactam ring structures (UP1 and
UP2).
Approximately 20-36% of an intravenous dose of 14C cefotaxime is excreted by the kidney as
unchanged cefotaxime and 15-25% as the DACM derivative, the major metabolite. Two other
urinary metabolites (UP1 and UP2) account together for about 20-25%. Faecal recovery accounts
for approximately 10% of the administered dose.
28
133.7
The DACM has been shown to contribute to 10-15% of the bactericidal activity of the parent
compound. It has no activity against Pseudomonas. UP1 and UP2 lack antibacterial activity.
In a study conducted on 22 healthy volunteers administered CLAFORAN and alcohol, there was
no disulfiram-like reaction.
Protein binding:
In an in vitro study using the dialysis chambers method, it was found that about 51% (range 3564%) of cefotaxime was bound to human serum proteins when concentrations ranged from 6.25
to 50 µg/mL. The bound percentage of the desacetyl metabolite was 16% to 32%, which is
approximately half of the parent compound. At a concentration of 100 µg/mL in serum, only a
small percentage of both the parent compound and its metabolite was bound; most probably the
portion of the protein molecules which bind them is saturated at this concentration.
TOXICOLOGY
Acute Toxicity
The acute toxicity of cefotaxime was determined in mice, rats, rabbits and dogs. The order of
toxicity by various routes was: i.v. > i.p. > s.c. No LD50s were found for per os or intramuscular
administration.
Common signs of toxicity were clonic and tonic convulsions, dyspnea, hypothermia and
cyanosis. There were almost no differences in sex or species. Cefotaxime was found to be twice
as toxic for newborns as it was for adults. The LD50 of the desacetyl derivative of cefotaxime
was determined in mice and found to be similar to cefotaxime with similar signs of intoxication.
Short-term Toxicity
In a 6-day acute toxicity study, cefotaxime was given intravenously to 3 groups of beagle dogs,
each consisting of 2 males and 2 females, at doses of 500 mg/kg for 2 days followed by
100 mg/kg for 4 days; and in a second group, 1000 mg/kg for 2 days followed by 250 mg/kg for
4 days. A third group of 4 dogs receiving physiological saline under the same conditions served
as control. The results of biochemical tests were unremarkable although there were transient
increases in urea and SGPT in a few treated males and in SGPT and alkaline phosphatase in 2
treated females.
At autopsy, microscopic examinations revealed superficial hemorrhages in the urethra of one
high dose male and a similar finding in the bladder of a female of the same group. The
hemorrhages were the apparent result of catheterization. The other high dose male had a scar on
the kidney and two scars on the bladder. Histological examination of the livers showed a few
areas of Kupffer cell hyperplasia in all treated males. A male and a female of the high dose group
had an abundance of glycogen in the hepatic parenchyma. Microscopic examination of the
29
kidneys showed slightly dilated proximal convoluted tubules without epithelial changes in one
male from each of the treated groups. Inflammatory and histocytic cells were noted in the
kidneys of one male from both treated groups.
Long-term Toxicity (30 days and 13 weeks)
The long-term toxicity of cefotaxime was investigated in 3 groups of 17 rats each of both sexes
receiving single daily subcutaneous doses of 300, 1000 and 3000 mg/kg for 1 month. At the
lowest dose, cefotaxime caused slight dilation of the cecum and very slight inflammatory
changes in the subcutaneous tissue at the sites of injection. In the 1000 mg/kg/day group, dilation
of the cecum, inflammatory changes at the injection sites accompanied by histopathological
change of the spleen and bone marrow, and tubular changes of the kidneys were observed. These
changes were seen infrequently and had a slight degree of severity. In rats treated with the
highest concentration of 3000 mg/kg/day, there was dilation of the cecum and extensive
subcutaneous hemorrhage at the injection sites. Secondary to the hemorrhagic and inflammatory
changes were an increase in neutrophils and a decrease in RBC count, hematocrit and
hemoglobin values, lymphoid hyperplasia of the spleen and increased erythropoiesis in the bone
marrow. Correspondingly, spleen weights were increased. After 2 weeks of reversal of treatment,
these changes were reduced. Fragments of epithelial cells and amorphous salts were observed in
urine sediment. Kidney weights were increased in all females. The kidneys had dilated tubules
and eosinopositive granular material in the proximal tubule epithelial cells.
In another study, cefotaxime was given under the same conditions to 3 groups of 15 rats each of
both sexes at dose levels of 400, 800 and 1600 mg/kg/day for 13 weeks. Different parameters
such as urinalysis, hematology, clinical chemistry and post-mortem examination of macroscopic
and microscopic examination of lesions showed similar results as observed above.
The intravenous toxicity of cefotaxime was studied in 4 groups of 15 male and 15 female rats
who received 0 to 1000 mg/kg/day in the caudal tail vein for 1 month. Except for some of the
animals given the highest dose of 1000 mg/kg who squeaked, tried to escape from the drug
injection and developed inflammatory changes at the sites of injection, cefotaxime
administration caused neither remarkable changes in behavior nor fatal cases in any of the drug
treated groups. In the hematological tests, plasma recalcification time and prothrombin time were
slightly shorter and the platelet count was decreased to a slight degree in the high dose rats in
both sexes although not statistically significant. Autopsies of both males and females exhibited
dose-dependent dilation of the cecum with retention of contents.
In some of these cases, hemorrhage, inflammatory changes and attenuation of the wall of the
cecum were observed microscopically. There were no spleen abnormalities except that lymphoid
hyperplasia was observed in all of the drug treated and control groups. However, in another
study done under the same conditions dose-related increases in spleen weights were reported.
Histologically, the spleens of some of the animals treated with 100 or 300 mg/kg for 30 days
were observed to have a moderate degree of white pulp activation.
30
The long-term intravenous and intramuscular toxicity of cefotaxime was further investigated in
groups of 3 male and 3 female beagle dogs treated with doses ranging from 0 to 300 mg/kg/day
for 30 consecutive days. When injected intravenously at 300 mg/kg/day, all dogs salivated
profusely and showed a clear nasal discharge. In dogs, the weight of the kidneys was increased.
One male and all 3 females of the high dose group had hyperemia with slight edema in the
cortical areas of the kidneys. Hemorrhage and hemorrhagic residues were seen at the site of
injection. Cefotaxime, when given intramuscularly at doses of 72 or 179 mg/kg/day, caused pain
at the site of injection in a few animals. The intensity of the lesions at the site of injection and the
frequency of their occurrences appear to be dose-related. Diarrhea was also noted in several dogs
treated with cefotaxime at these two doses.
In another study, cefotaxime was injected intravenously to beagle dogs - 3 animals/sex/group - at
doses of 500, 1000 and 1500 mg/kg/day for 13 weeks. As observed earlier, the mid- and highdose dogs salivated during the injection of the compound and had occasionally soft stools. At
week 11, one female treated with 1500 mg/kg/day showed signs of anemia; palpation suggested
a hemorrhagic disorder in the area of the spleen. The hemograms were consistent with an acute
hemorrhage. Renal lesions graded minimal to slight were reported to occur in all drug groups but
not in all dogs. Some dogs treated with 1000 and 1500 mg/kg/day showed a slight increase of
extra medullary hematopoiesis in the spleens. In prescapular lymph nodes, an increase of focal
lymphadenitis and erythrophagocytosis were seen in treated dogs. In male dogs, the lymph nodes
showed increased activity of the germinal centers and hyperplasia of medullary plasmacytes.
Groups of 4 male and 4 female beagle pups further received subcutaneous injections of
cefotaxime at doses of 0 to 1500 mg/kg/day for 30 consecutive days. A dose-related response to
pain, both in intensity and duration was observed. Post-mortem examinations revealed
hemorrhage and edema at the injection site.
The long-term toxicity of cefotaxime was compared with that of cephaloridine and cephalothin
in 6 groups of 3 male and 3 female rabbits treated intravenously, daily for 30 days.
Cefotaxime doses ranged from 0 to 120 mg/kg/day while cephaloridine and cephalothin were
given at the daily dose of 120 mg/kg/day. In the cefotaxime group, one rabbit died at 30 mg/kg,
three at 60 mg/kg and two at 120 mg/kg. Two rabbits died in the cephaloridine and one in the
cephalothin group. Diarrhea was observed in all treated groups. Neither cefotaxime nor
cephalothin produced microscopic lesions. Two rabbits given cephaloridine had myocardial
necrosis.
31
Chronic Toxicity
The chronic toxicity of cefotaxime was investigated in rats and dogs over a period of 6 months.
Groups of 25 male and 25 female rats received subcutaneous injections of cefotaxime at doses of
0, 40, 100 and 250 mg/kg/day 7 days a week for 26 weeks. On the whole, chronic administration
of cefotaxime for 6 months was well tolerated. Rats treated with 250 mg/kg/day showed a slight
and transient depression of body weight gain in both males and females. Local tolerance
reactions were noted in animals treated with 100 or 250 mg/kg from the third week to the end of
the study. Microscopic examination of these tissues taken from the high dose animals showed
marked inflammatory subcutaneous sclerosis often accompanied by the presence of hematomas
and muscular atrophy.
One male treated with 250 mg/kg had to be killed after 4 months of treatment because of sudden
deterioration of its general condition. Histopathological examination revealed ulceration of the
stomach mucosa, congestion of the liver and a subcapsular interstitial scar in the kidney.
Otherwise, there was no mortality in any of the groups.
The chronic toxicity of cefotaxime was further examined in dogs (4 animals/sex/group) when
given intramuscularly at doses of 0, 40, 100 or 250 mg/kg/day 7 days a week for 26 weeks.
Reaction of pain was observed in all dogs in the highest dosage groups immediately following
the injection. Histopathologic lesions at the injection sites showed a dose-related inflammatory
response. No dogs died during the treatment. Numerous variations in hematology, coagulation
and biochemical values were observed in individual animals. The variations were, however,
within normal limits and the distribution in the two groups did not suggest an effect of the
compound.
Fertility and Reproduction
Cefotaxime was administered intravenously at doses of 0, 100, 400 and 2000 mg/kg/day to
groups of 22-24 male mice for 9 weeks prior to and including mating and to groups of 23-24
females for 2 weeks before mating and through Day 6 of gestation. Under these conditions the
copulation and conception rate in the treated groups were comparable to those in the control.
Treated groups did not differ from controls in the number of corpora lutea, resorptions and live
and dead fetuses. Body and placental weights, crown-rump lengths and sex ratio of the live
fetuses from treated females corresponded with those found in the control group. The live fetuses
at each dosage level showed no external, visceral or skeletal abnormalities considered to be
related to the administration of the compound.
In a similar study done in rats with 20-25 animals/sex/group, cefotaxime at doses of 0, 40, 100 or
250 mg/ kg/day did not alter the sexual behavior and reproductive function of the parents (F0) or
of the F1 offspring.
32
Peri and Postnatal Behavior
Two perinatal and postnatal studies were conduced with cefotaxime in 104 mated rats. In the
first study, dosage levels of 150, 300 and 600 mg/kg were administered by intravenous injection
twice daily at a minimum of 6 hours apart beginning on the 15th day of gestation and continuing
throughout gestation and lactation.
No effects attributable to treatment with cefotaxime were observed on maternal appearance,
behavior, survival, fertility, length of gestation or number of live and non-viable pups. Maternal
body weights were comparable during the gestation and lactation periods for cefotaxime-treated
groups and the control groups with the exception of slightly reduced body weight gains in the
1200 mg/kg/day treated rats during the first 5 days of treatment and Days 12 through 21 of
lactation. Reduced mean pup body weights were noted in this group at birth through weaning.
No other biologically meaningful effects were noted from intravenous injections of cefotaxime at
1200 mg/kg/day or less during the later portion of gestation through weaning.
Under a similar protocol, cefotaxime was given intramuscularly at doses of 0, 40, 100 or
250 mg/kg/day. At these doses, no effects of cefotaxime were observed on the peri and postnatal
behaviour of the mothers and the general condition and viability of the offspring.
Teratology
Cefotaxime was given intravenously at doses of 300, 600 and 1200 mg/kg/day to groups of 2023 pregnant mice, and to pregnant rats intravenously (300, 600 and 1200 mg/kg/day) or
intramuscularly (40, 95 or 210 mg/kg/day) from Day 6 through Day 15 or 18 of gestation. No
findings indicative of a compound-related teratogenic effect were noted in any of the fetuses at
necropsy or during the visceral and skeletal examinations. On the basis of these studies,
cefotaxime was not considered embryotoxic or teratogenic when administered parenterally in
mice and rats at levels up to 1200 mg/kg/day.
The teratogenic effect of cefotaxime was further studied in pregnant rabbits treated
intramuscularly with daily doses of 25, 50 and 90 mg/kg for sequential periods of 4-7 days
throughout the phase of embryogenesis. Maternal toxicity and embryotoxicity were recorded in
groups dosed with 50 mg/kg and higher. Lower fetal weights were recorded in the groups dosed
with 90 mg/kg/day and a few malformations or simple abnormalities appeared in all groups,
including the controls. Rabbits are particularly sensitive to cephalosporins in general and are
therefore inappropriate to test the reproductive and teratogenic effects of these compounds.
Mutagenicity
Possible mutagenic effects of cefotaxime were investigated using the micronucleus test in mice
and the Ames test in bacterial strains. No mutagenicity could be attributed to cefotaxime using
these two standard methods.
33
Carcinogenicity
Long-term studies in animals have not been performed to evaluate the carcinogenic potential of
cefotaxime.
Nephrotoxicity
The potential nephrotoxicity of cefotaxime was compared with that of cephaloridine and
cephalothin in rabbits (2 males and 2 females per group) when given daily intramuscularly at
doses of 220, 200 and 190 mg/kg, respectively for 7 consecutive days. The 3 antibiotics induced
emaciation in some animals and death of one rabbit in each treated group. Only in the animals
treated with cephaloridine did the histological examination reveal tubular necrosis. No
morphological substance-induced organ changes were detected in the rabbits treated with
cefotaxime or cephalothin.
A potent diuretic agent, furosemide, has been shown to enhance the nephrotoxicity of
cephaloridine in animals. Studies were conducted in mice and rats to evaluate the effect of a
single parenteral dose of 20 mg/kg furosemide given 15 minutes before the injection of
cefotaxime on renal function and renal histology. Cefotaxime concentrations were 2000 and
4000 mg/kg in mice and 2500 and 5000 mg/kg in rats. Microscopic examination of the kidneys
revealed some dilated tubules in the cortex and the medulla and some hyalin casts in control and
all treated groups regardless of furosemide administration.
The nephrotoxicity of the combined administration of cefotaxime (1000 mg/kg/day i.v.) with
gentamicin (30 mg/kg/day i.m.) or furosemide (100 mg/kg/day p.o.) was studied in groups of
16 female rats for 28 consecutive days. Single treatments with each drug, alone or in
combination with cefotaxime produced neither death nor abnormalities in behavior or
appearance, nor did they affect body weight gain and food consumption. Main histopathological
findings were: occurrence of eosin-positive material (slight degeneration) in the epithelial cells
of the proximal convoluted tubules, considered to be due to a change in the lysosomes, in the
group given cefotaxime alone; interstitial inflammation and slight focal necrosis in the proximal
tubules in rats injected only with gentamicin; and calcification of the distal convoluted tubules in
animals administered furosemide alone. The concurrent administration of cefotaxime with
gentamicin or furosemide produced combinations of the above described changes, each of which
was not enhanced either in incidence or in extent.
34
Tolerance studies
The local intravenous tolerance of cefotaxime was investigated in rats and dogs. Rats
(15 animals/sex/ group) injected intravenously in the caudal vein daily for 30 days with
cefotaxime at doses of 125, 500 and 1000 mg/kg in physiological saline and those being used as
controls showed a slight but dose-related degeneration of the epidermis, hemorrhage,
perifollicular edema and inflammatory cell infiltration of the dermis and subcutaneous tissues. In
dogs, however, the intravenous tolerance was not dose-related and did not differ from that of
controls. The minimal lesions observed at the injection sites following a 13 week administration
of 0 to 1500 mg/kg/day were interpreted as being caused by the trauma of repeated i.v. injections
rather than by cefotaxime itself.
The local intramuscular tolerance of cefotaxime was compared with that of cephaloridine in
2 groups of 10 male rats given a single injection of 100 mcg per rat. Cefotaxime caused only
minor and transient local tissue damage - necrotic areas, fragmentation of muscle fibers and
inflammation - while similar doses of cephaloridine produced more severe and persistent
damage.
The local intramuscular tolerance of 1000 mg/kg cefotaxime was further investigated in groups
of 3 male and 3 female rabbits when given in a single injection with or without 1% lidocaine.
One rabbit of each group died of diarrhea and no substance-induced organ lesions were observed
at the end of a 3 week follow-up period. This study showed that the tolerance to 1000 mg/kg
cefotaxime in rabbits was not affected by administration in a 1% lidocaine solution.
The sub-occipital tolerance of cefotaxime was also compared with that of cephaloridine when
given as a single sub-occipital injection to groups of 10 rats at doses ranging from 2.5 to
19 mg/kg. Doses of 2.5 and 5 mg/kg cephaloridine and 19 mg/kg cefotaxime caused prostration,
respiratory impairment, hyperventilation, tremors, and convulsions. At each of these dosage
levels, 40-60% of animals per group died a few minutes following the injections. Doses of 2.5, 5
and 9.5 mg/kg cefotaxime and 1.25 mg/kg cephaloridine were satisfactorily tolerated.
To investigate the intrathecal tolerance, 50 mg cefotaxime was administered as a single dose
through the foramen magnum to 2 male and 2 female beagles. All dogs treated with cefotaxime
showed slight tetanoid convulsions for about 1 hour towards the end of anesthesia. Histological
examinations did not reveal any compound-related impairment of the CNS, the spinal cord and
meninges.
The renal tolerance of cefotaxime was further compared with that of cephaloridine in groups of
2 male and 2 female beagle dogs when given as a single 1000 mg/kg i.v. injection. In contrast to
cephaloridine, cefotaxime caused only a slight and transient reduction of PAH clearance.
Creatinine clearance remained unchanged and the urinary output was not disturbed at any time.
Combination LD50 Study
The toxicity of combinations of cefotaxime and gentamicin when studied in rats did not appear
very different from the toxicities exhibited by the individual components.
35
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